Part of the mechanism underlying the therapeutic effect of subthalamic nucleus (STN) high frequency stimulation (HFS) involves the activity of the basal ganglia output structures. The general idea is that STN's burst activity leads to an increased activity of the basal ganglia output nuclei and that HFS reverses this. However, the published data sets conflict. Here, we addressed the question which effect STN HFS had on the overall substantia nigra pars reticulata (SNr; one of the basal ganglia output nuclei) activity, in rats rendered Parkinsonian by 6-hydroxydopamine (6-OHDA) injections in the striatum, We used a marker for metabolic activity, cytochrome C oxidase (COX). The expression of COX in the SNr of Parkinsonian rats was significantly higher as compared to sham-operated rats. However, in Parkinsonian rats with STN HFS, expression of COX was significantly lower as compared to non-stimulated Parkinsonian rats, and was comparable to the level of expression in sham-operated rats. These results show that STN HFS decreased the overall activity of the basal ganglia output nucleus in dopamine-depleted rats. (C) 2009 Elsevier B.V. All rights reserved.